Project Summary Depression creates a significant burden of morbidity and mortality worldwide, but current pharmacologic treatments are suboptimal even when combined with psychological intervention. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a powerful, new chemogenetic tool that is transforming neuropsychiatric research. However, current DREADD technology requires injection of a viral-vector into the brain, limiting clinical application. The eye presents a promising alternate route of DREADD vector administration to treat depression, as i) the retina can be accessed without the risk of invasive brain surgery, and ii) the retina is a major input to a signaling pathway that we previously identified as potentially involved in least some forms of depression. Indeed, we found that we can express Gq (excitatory) DREADDS in retinal ganglion cells (RGCs) with a simple intravitreal AAV injection. Then, using the retina as a chemogenetic target, we prevented the emergence of depression normally induced by prolonged light deprivation by stimulating these retinal DREADDs. We hypothesize that this anti-depressive effect occurs via a retina > suprachiasmatic nucleus (SCN) > dorsomedial hypothalamus (DMH) > locus coeruleus (LC) circuit. We refer to this pathway as the photic regulation of arousal and mood (PRAM) pathway. Additionally, we found that activating the retinal source of the PRAM pathway increases the tonic firing rate of LC neurons, and prevents damage in LC neurons (as seen with p85-PARP) and loss of D?H+ fibers in prefrontal cortex (PFC) that otherwise occurs after light deprivation. A goal of this proposal is to test the hypothesis that DREADD activation of RGCs will also reverse depressive-like behavior; our initial results indicate that this may indeed be the case. This would be important for broad translational application of our PRAM approach. We also will test the roles of LC noradrenergic, and SCN, neurons in the ability of PRAM stimulation to decrease depressive-like behaviors. Our proposed studies will lead to a better understanding of retina-associated pathways in the brain that influence mood. Because these studies employ DREADD technology to manipulate the retina for the purpose of controlling brain activity, it represents a novel but simple approach to the precise control of neural networks, while eliminating the need for brain surgery. Therefore, the development of this technique could have great impact on clinical approaches to treating depression. As LC is involved in a wide array of neuropsychiatric disorders, results will also have implications for new ways to treat a variety of mental health issues.